E. J. Warawa in U.S. Pat. No. 3,560,510 discloses certain 3-amino-2-benzhydryl-quinuclidines as being useful as diuretic agents, with the corresponding unsubstituted 3-benzylamino compounds acting as intermediates for same. Additionally, E. J. Warawa et al. in the Journal of Medicinal Chemistry, Vol. 18, p. 587 (1975) extends this work to other members of the series wherein the 3-amino moiety is either ethylamino, .beta.-phenylethyl amino, .beta.-isopropylamino, or 2-furfurylamino, but in no instance is there any substitution on the phenyl group itself and the 2-benzhydryl moiety is always symmetrically substituted (or unsubstituted).
Furthermore, neither of the aforementioned documents teaches or suggests any of these compounds to be useful as substance P antagonists.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt stimulatory action on smooth muscle tissue. More specially, substance P is a pharmaceutically active neuropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has recently been shown to be involved in the transmission of pain or migraine (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, Vol. 25, p. 1009 (1982)), as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, and in gastrointestinal disorders and diseases of GI tract, like ulcerative colitis and Crohn's diseases, etc (see D. Regoli in "Trends in Cluster Headache" edited by F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85-95).
In the recent past, some attempts have been made to provide peptide-like substances that are antagonists for substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases listed above. The peptide-like nature of such substances make them too labile from a metabolic point of view to serve as practical therapeutic agents in the treatment of disease. The non-peptidic antagonists of the present invention, on the other hand, do not possess this drawback, being far more stable from a metabolic point of view than the previously-discussed prior art agents.
Among documents of interest regarding the present invention, there are WO 90/05729 (corresponding to U.S. Pat. No. 5,162,339), JP (appln.) 325237/91 (corresponding to PCT Patent Publication No. WO 92/20676) and JP (appln.) 065337/92. (All documents cited herein, including the foregoing, are incorporated herein by reference in their entireties for all purposes.)
Particularly, WO 90/05729 discloses a series of cis-3-[(cyclic)methylamino]-2-[(.alpha.-substituted)arylmethyl]quinuclidin es including 2-benzhydryl derivatives, 2-substituted benzhydryl derivatives (wherein the substituents were alkyl, alkoxy, halogen and the like), 2-(bis-(2-thienyl)methyl) derivatives and the like.
JP (appln.) 325237/91 discloses mainly a series of 3-[2-methoxy-5-(substituted)benzylamino]-2-benzhydryl quinuclidines including 4-alkenyl derivatives, 6-phenethyl derivatives, 5- and 6-dialkylaminocarbonyl derivatives, 5-dialkylaminoalkyl derivatives, 6-hydroxyalkyl derivatives, 5-alkylaminocarbonyl derivatives, 5-aminocarbonyl derivatives, 5-carboxyl derivatives, 5- and 6-alkoxycarbonyl derivatives, 5-(N-alkoxy-N-alkyl)aminocarbonyl derivatives, 5-morpholinocarbonyl derivatives and the like.
Additionally, the quinuclidine compounds disclosed in JP (appln.) 325237/91 have various kinds of substituents also at the 5-position on the benzylamino moiety, i.e. alkoxy (methoxy), alkyl (isopropyl), alkylthio (methylthio), halosubstituted alkoxy (trifluoromethoxy), halogen, alkylsulfinyl (methylsulfinyl), dialkylamino (dimethylamino) and the like.
Furthermore, it shows that compounds disclosed in both WO 90/05729 and JP (appln.) 325237/91 have substance P antagonist activity, anti-inflammatory activity and anti-psychotic activity.
Under the circumstances, the present inventors have worked to prepare compounds useful as substance P antagonists, and after extensive research, have succeeded in synthesizing a series of compounds as will be disclosed in detail herein.